Robust Salmonella metabolism limits possibilities for new antimicrobials

Becker, Daniel E.; Selbach, Matthias; Rollenhagen, Claudia; Ballmaier, Matthias; Meyer, Thomas F.; Mann, Matthias; Bumann, Dirk

doi:10.1038/nature04616

Cited by 311 publications

(308 citation statements)

References 32 publications

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“…The properties of this core show that the reactions that are most difficult to bypass do not allow the organism to survive in specific environments, but they are essential to life in multiple environments. Computational and experimental studies have tried to identify common essential reactions across a small number of organisms to develop antibiotics (37,54). Our identification of an absolutely superessential core of reactions goes beyond these analyses.…”

Section: Discussionmentioning

confidence: 99%

“…This observation is consistent with our earlier observations that most superessential reactions are environment-general. Moreover, enzyme-coding genes of 114 of 125 absolutely superessential reactions have experimentally been confirmed as essential in at least one of three well-studied organisms, namely S. enterica serovars (37,55), M. tuberculosis H37Rv (56,57), and P. aeruginosa (58, 59) (Dataset S6). Furthermore, a significantly larger number of absolutely superessential reactions than expected by chance alone (mean = 83%) is encoded by a majority of sequenced prokaryotic genomes.…”

Section: Discussionmentioning

confidence: 99%

“…Glycerol-3-phosphate acyltransferase, encoded by plsB, plays a role in phospholipid synthesis and is essential in E. coli (11) and S. typhirium (37) in the murine in vivo infection model. The enzyme uses fatty acyl-ACP or acyl-CoA thioesters to form acylglycerol-3-phosphate, and it is mainly limited to γ-proteobacteria (38), which explains its low genome occurrence index.…”

Section: Genes Responsible For Superessential Reactions Occur In Mostmentioning

confidence: 99%

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Superessential reactions in metabolic networks

Barve

Rodrigues²,

Wagner³

2012

Proc. Natl. Acad. Sci. U.S.A.

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The metabolic genotype of an organism can change through loss and acquisition of enzyme-coding genes, while preserving its ability to survive and synthesize biomass in specific environments. This evolutionary plasticity allows pathogens to evolve resistance to antimetabolic drugs by acquiring new metabolic pathways that bypass an enzyme blocked by a drug. We here study quantitatively the extent to which individual metabolic reactions and enzymes can be bypassed. To this end, we use a recently developed computational approach to create large metabolic network ensembles that can synthesize all biomass components in a given environment but contain an otherwise random set of known biochemical reactions. Using this approach, we identify a small connected core of 124 reactions that are absolutely superessential (that is, required in all metabolic networks). Many of these reactions have been experimentally confirmed as essential in different organisms. We also report a superessentiality index for thousands of reactions. This index indicates how easily a reaction can be bypassed. We find that it correlates with the number of sequenced genomes that encode an enzyme for the reaction. Superessentiality can help choose an enzyme as a potential drug target, especially because the index is not highly sensitive to the chemical environment that a pathogen requires. Our work also shows how analyses of large network ensembles can help understand the evolution of complex and robust metabolic networks.drug resistance | drug target identification | essential reactions

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genes Responsible For Superessential Reactions Occur In Mostmentioning

confidence: 99%

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Superessential reactions in metabolic networks

Barve

Rodrigues²,

Wagner³

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The plasmid pCol1B9 SL1344 is responsible for horizontal gene transfer via conjugation to E. coli during infection of the murine gut (20). The relatively high proportion of regulatory and metabolic genes in S. Typhimurium contributes to the physiological versatility of this robust pathogen (Dataset S1) (21).…”

Section: Sl1344mentioning

confidence: 99%

The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium

Kröger¹,

Dillon²,

Cameron³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

381

427

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More than 50 y of research have provided great insight into the physiology, metabolism, and molecular biology of Salmonella enterica serovar Typhimurium (S. Typhimurium), but important gaps in our knowledge remain. It is clear that a precise choreography of gene expression is required for Salmonella infection, but basic genetic information such as the global locations of transcription start sites (TSSs) has been lacking. We combined three RNAsequencing techniques and two sequencing platforms to generate a robust picture of transcription in S. Typhimurium. Differential RNA sequencing identified 1,873 TSSs on the chromosome of S. Typhimurium SL1344 and 13% of these TSSs initiated antisense transcripts. Unique findings include the TSSs of the virulence regulators phoP, slyA, and invF. Chromatin immunoprecipitation revealed that RNA polymerase was bound to 70% of the TSSs, and two-thirds of these TSSs were associated with σ 70 (including phoP, slyA, and invF) from which we identified the −10 and −35 motifs of σ 70 -dependent S. Typhimurium gene promoters. Overall, we corrected the location of important genes and discovered 18 times more promoters than identified previously. S. Typhimurium expresses 140 small regulatory RNAs (sRNAs) at early stationary phase, including 60 newly identified sRNAs. Almost half of the experimentally verified sRNAs were found to be unique to the Salmonella genus, and <20% were found throughout the Enterobacteriaceae. This description of the transcriptional map of SL1344 advances our understanding of S. Typhimurium, arguably the most important bacterial infection model. transcriptional mapping | noncoding RNA | posttranscriptional regulation | pathogenicity | genome sequence

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“…However, at least in terms of antimicrobial therapies, progress will be challenging. For example, Becker and coworkers [80] recently surveyed 700 Salmonella enterica metabolic enzymes as expressed in vivo within a model host system, and came to the conclusion that of the subset of genes that played a role in virulence, almost none were likely to yield new targets for antibiotics. This study emphasized a further subset of enzymes associated with virulence that were also conserved across other human pathogens.…”

Section: Biological Relevancementioning

confidence: 99%

Mass Spectrometry-Based Proteomics and its Application to Studies of Porphyromonas gingivalis Invasion and Pathogenicity

Lamont¹,

Meilă²,

Xia³

et al. 2006

IDDT

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Porphyromonas gingivalis is a Gram-negative anaerobe that populates the subgingival crevice of the mouth. It is known to undergo a transition from its commensal status in healthy individuals to a highly invasive intracellular pathogen in human patients suffering from periodontal disease, where it is often the dominant species of pathogenic bacteria. The application of mass spectrometry-based proteomics to the study of P. gingivalis interactions with model host cell systems, invasion and pathogenicity is reviewed. These studies have evolved from qualitative identifications of small numbers of secreted proteins, using traditional gel-based methods, to quantitative whole cell proteomic studies using multiple dimension capillary HPLC coupled with linear ion trap mass spectrometry. It has become possible to generate a differential readout of protein expression change over the entire P. gingivalis proteome, in a manner analogous to whole genome mRNA arrays. Different strategies have been employed for generating protein level expression ratios from mass spectrometry data, including stable isotope metabolic labeling and most recently, spectral counting methods. A global view of changes in protein modification status remains elusive due to the limitations of existing computational tools for database searching and data mining. Such a view would be desirable for purposes of making global assessments of changes in gene regulation in response to host interactions during the course of adhesion, invasion and internalization. With a complete data matrix consisting of changes in transcription, protein abundance and protein modification during the course of invasion, the search for new protein drug targets would benefit from a more comprehensive understanding of these processes than what could be achieved prior to the advent of systems biology. KeywordsPorphyromonas gingivalis; gingival epithelial cells; proteomics; posttranslational modification; protein expression; invasion; database search algorithm; review; MudPIT Diseases that originate at mucous membranes and involve constituents of the normal microbiota are often multifactorial in origin. Nowhere is this more apparent than in the human oral sub-gingival crevice. In this environment, hundreds of bacterial species interact with the multicompartmental periodontal tissues that provide supporting structures for the teeth. Under normal conditions, the host tolerates this microbial burden and the periodontal tissues remain healthy. However ecological shifts can occur that cause the microbiota to acquire a pathogenic *Address correspondence to this author at the Department of Chemical Engineering, Box 355014, University of Washington, Seattle, Washington 98195; Telephone: (206) 616 8071; E-mail mhackett@u.washington.edu. NIH Public Access Author ManuscriptInfect Disord Drug Targets. Author manuscript; available in PMC 2009 April 7. Published in final edited form as:Infect Disord Drug Targets. 2006 September ; 6(3): 311-325. NIH-PA Author ManuscriptNIH-PA Author Manuscript ...

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Robust Salmonella metabolism limits possibilities for new antimicrobials

Cited by 311 publications

References 32 publications

Superessential reactions in metabolic networks

Superessential reactions in metabolic networks

The transcriptional landscape and small RNAs of Salmonella enterica serovar Typhimurium

Mass Spectrometry-Based Proteomics and its Application to Studies of Porphyromonas gingivalis Invasion and Pathogenicity

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